Pharmaceutical Bioequivalence Studies: Ensuring Safety, Effectiveness and High Quality

Abstract

Poor quality medicines are a global problem affecting both developed and developing countries. Governments and the health authorities are focusing on the spread of counterfeit medicines, as it is a threat to patients and funds criminal activities. Recently questions have been raised about using generic substitutes, especially for Narrow Therapeutic Index Drugs (NTIDs), such as ciclosporin. In-vitro dissolution testing was undertaken to identify differences in dissolution performance between branded and generic ciclosporin capsules. Dissolution testing of the capsules was carried out according to the USP guidelines. According to the USP not less than 80% of the labelled amount of ciclosporin should dissolve in 90 min. The samples were analysed using a HPLC method. Two ciclosporin generic products showed less than the minimum percentage of labelled amount < 80%. Statistical analysis showed significant differences (p<0.0001) of the mean percentage content between brand and generic. Investigations were carried out to detect impurities in ciclosporin capsules using LC-MS. Concentrations of inactive ingredients such as sorbitol were variable between capsules. One from South America, manufactured in central Asia, showed contamination with a plant product (Zizyphine A). the synthetic intermediate (Delcorine) was found to be more than 1000 fold higher in the generic product compared to reference capsules (p<0.001). In 2013, the FDA warned of the possible fatal effect of azithromycin. LC-MS quantification for azithromycin tablets were carried out in order to quantify azithromycin content in different products. A bioequivalence study in man, confirmed that generic (Mazit) capsules were bioequivalent with brand (Zithromax™) capsules. Based on the results presented in this thesis, HPLC and LC-MS proved suitable approaches for analysis of drugs and their unknown impurities in brand, generic and counterfeit medicines. Some ciclosporin preparations did not contain the mass labelled. Therefore, switching between branded and generic ciclosporin may lead to undesirable effect.